3-tropanyl-2-aminophenylacrylate compounds



United States Patent 3,458,507 3-TRU?ANYL-2-AMINQPHENYLACRYLATECOMPOUNDS Henry (I. Caldwell, Ambler, and William G. Groves,

Norristown, Pa., assignors to Smith Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Nov.1, 1967, Ser. No. 679,656 lint. Cl. (307d 43/06; Alk 27/00 US. Cl.260-240 6 Claims ABSTRACT OF THE DISCLOSURE Substituted 3-tropanyl 2aminophenylacrylate esters having gastrointestinal spasmolytic activity,the substituent on the 3 carbon atom of the 2-phenylacrylic acidderivatives being hydrogen, phenyl, furyl, thienyl and pyridyl. Methodof preparation comprises reacting the properly substitutednitrophenylacetic acid with paraformaldehyde or an aromatic aldehyde,treating the formed acid with tropine or thiotropine and converting theresulting ester to the final amino derivative by hydrogenating withRaney nickel.

This invention relates to novel substituted 3-tropanyl-2-aminophenylacrylate esters which have useful pharmacodynamic activity.More specifically, the compounds of this invention possessgastrointestinal spasmolytic activity as demonstrated in standard animalpharmacological test procedures. For example, in the modified Janssentest for the inhibition of fecal pellet count, spasmolytic activity wasobserved as doses of 3.2 mg./kg. and 51.2 ing/kg. in mice.

. These novel compounds are particularly advantageous because theyproduce the spasmolytic activity without the concomitant mydriatic andantisalivary side elfects which are common to knownanticholinergic-antispasmodic drugs. Prior to the present invention,there has been a great need for compounds which produce spasmolyticactivity without the usual anticholinergic side effects such as forexample, dry mouth, blurred vision and urinary retention which arecommon to known anticholinergic-antispasmodic drugs. The need of safeand effective compounds free of the above-noted side effects and havingspasmolytic activity has been great.

compared to a closely related congener such as 3-tropanyl-2-p-ch1orophenyl-3-phenylacrylate. The following results in mice wereobtained.

Spasmo- MLD lytic Thera- (toxic dose peutic dose) (EDso) index3-tropanyl-2rp-aminophenyl-3- phenylaerylate 512 5. 73-tr0panyl-2-p-ehlorophenyl-3- phenylacrylate 16. 7 12 It can be seenthat the aminophenylacrylate derivative of this invention has a muchgreater margin of safety than the known chlorophenyl congener.

The novel substituted amino tropanyl esters of this invention arerepresented by the following general formula:

Formula 1 when X represents OXygen or sulfur;

R and R represent hydrogen or a lower alkyl group having from 1 to 4carbon atoms;

R represents hydrogen, phenyl, furyl, thienyl or pyridyl.

The substituted 3-tropanyl-2-aminophenylacrylates are prepared accordingto the following synthetic procedure:

3-tropanyl esters of atropic and thiotropic acid are known in theliterature as set forth in US. Patent No. 3,308,129. The novelty of thecompounds of the present invention resides, however, in the presence ofa basic amino group on the phenyl moiety of the a carbon atom. Thesenovel compounds have a greater therapeutic index than the above-notedprior art compounds. In brief, theratio of the minimum lethal dose tothe eifective spasmolytic dose is greater, thereby resulting in a muchsafer compound. Further, 3-tropanyl-2-p-aminophenyl-3-phenylacrylate, arepresentative compound of this invention was acetic anhydride and usinga tertiary amine such as triethylamine, pyridine or N,N-dimethylanilineas a catalyst.

The 2-nitrophenylacrylic acid derivative is then converted to thedesired 3-tropanyl-Z-nitrophenylacrylate by preparing the acyl chlorideor anhydride and reacting with tropine, thiotropine or a salt thereof.The resulting 3-tropanyl-2-nitrophenylacrylate derivative is thenconverted to the desired 2-aminophenylacrylate by hydrogenating overRaney nickel.

Alternatively, 3-tropanyl-Z-p-nitrophenylacrylate can be prepared by themethod outlined in Schwenker, Archivder Pharmazie, 298, 826 (1965).

The invention also includes nontoxic pharmaceutically acceptableaddition salts of the above-defined bases formed with organic andinorganic acids. Such salts are easily prepared by methods known to theart. The base is reacted with either the stoichiometric amount oforganic or inorganic acid in aqueous miscible solvent, such as acetoneor ethanol, with isolation of the salt by concentration and cooling oran excess of the acid in aqueous immiscible solvent, such as ethyl etheror chloroform, with the desired salt separating directly. Exemplary ofsuch organic salts are those with maleic, fumaric, benzoic, ascorbic,pamoic, succinic, bismet'hylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic and theophylline acetic acids as well as with the8-halotheophyllines, for example, 8-chlorotheophylline and 8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids. These salts may also be prepared by the classical method ofdouble decomposition of appropriate salts which is well known to theart.

Further, exemplary of salts are nontoxic quaternary ammonium salts ofthe above-defined bases formed with ph-armacologically acceptable loweralkyl or aralkyl esters of, for exmple, sulfuric, hydrohalic andaromatic sulfonic acids. These salts are prepared by treating a solutionof the base in a suitable solvent, such as chloroform, acetone, benzene,toluene or ether with an excess of an organic ester of sulfuric,hydrohalic or aromatic sulfonic acid. This reaction is carried out mostadvantageously at a. temperature in the range of from about 25 C. toabout 115 C. Exemplary of such reactive esters are lower alkyl halidesof a maximum of 8 carbon atoms such as methyl chloride, methyl bromide,methyl iodide, ethyl chloride, propyl bromide, butyl chloride, isobutylchloride, ethylene bromohydrin, ethylene chlorohydrin, allyl bromide,methallyl bromide, crotyl bromide, benzyl chloride, benzyl bromide,naphthylmethyl chloride, phenethyl bromide, dimethyl sulfate, diethylsulfate, methyl benzene sulfate and ethyl toluene sulfonate.

The novel compounds of this invention may be administered orally orparenterally in conventional dosage unit forms such as tablets,capsules, inject-ables or the like, by incorporating the appropriatedose of a compound of Formula 1 with carriers according to acceptedpharmaceutical practices. The substituted amino tropanyl esters ofFormula 1 will be present in an amount to produce gastrointestinalspasmolytic activity. Preferably the dosage unit forms will contain thecompounds of Formula 1 in an amount of from about 2.0 mg. to about 100mg., advantageously from about mg. to about 50 mg. Advantageously equaldaily doses are administered one to four times daily to provide a dailydosage regimen.

The following examples are not limiting but are illustrative of thisinvention and the procedures for their preparation. Other variations ofthis invention will be obvious to those skilled in this art.

Example 1 To a mixture containing 31.8 g. of p-nitrophenylacetic acid,ml. of benzaldehyde and 16.2 ml. of triethyl- .4 amine is added withcooling 44 ml. of acetic anhydride. The mixture is stirred forapproximately /2 hour and heated in an oil bath at 70 C. The temperatureis raised to C. over a /2 hour period and heating continued forapproximately five hours. The solution is cooled and made acidic withconcentrated hydrochloric acid. The crude acid is filtered, dried andrecrystallized from alcohol to yield 2-p-nitrophenyl-B-phenylacrylicacid.

A suspension of 13.0 g. of 2-p-nitrophenyl-3-phenylacrylic acid, 20 ml.of dry benzene and 10 ml. of thionyl chloride is warmed gently until asolution results. The clear solution is refluxed for about an hour andthe excess thionyl chloride and benzene is removed by asperator. Thesolution is further washed with three separate portions of dry benzene.To the resulting oil is added 9.1 g. of tropine hydrobromide and themixture is then chilled. To this mixture is added 20 ml. of dry pyridineand the solution is stirred for about /2 hour at room temperature andthen at 60 C. to 70 C. for one hour. The mixture solidifies during thisprocess and 10 ml. of dry pyridine is added. Then 100 ml. of water isadded and the solution is warmed and treated with charcoal. The solutionis made basic and the free base is extracted with ether and dried. Thepyridine is removed by treatment with several portions of benzene. Thebenzene is distilled off to yield3-tropanyl-2pnitrophenyl-3-phenylacrylate.

An ethereal solution of the free base is treated with hydrogen chlorideto yield the hydrochloride salt.

A solution of 14 g. of 3-tropanyl-2-p-nitrophenyl-3- phenyl-acrylatehydrochloride in 250 ml. of methanol is hydrogenated over Raney nickel.The reaction mixture is warmed and filtered. The precipitate formed oncooling is recrystallized from methanol to yield3-tropanyl-2-paminophenyl-3-phenylacrylate hydrochloride as a yellowsolid having a melting point of 265 C. to 266 C.

Example 2 Similarly following the procedure outlined in Example 1, 25.5g. of m-nitrophenylacetic acid was employed as the starting material toyield 3-tropanyl-Z-m-aminophenyl- 3-phenylacrylate having a meltingpoint of 230 C.- 231 C.

Example 3 To a mixture under nitrogen containing 500 ml. of anhydrousether, 27.6 g. of magnesium turnings and 11 drops of ethyl bromide isadded 15 ml. of isopropyl chloride. The mixture is warmed until thereaction proceeds and 87 ml. more of isopropyl chloride is added and themixture refluxed moderately for approximately one hour. A solution of90.6 g. of p-nitrophenylacetic acid in 500 ml. of dry benzene is thenadded and the mixture further refluxed for approximately two hours. 50.0g. of paraformaldehyde is then distilled into the mixture with the aidof a stream of dry nitrogen. The thick solution is stirred for about anhour after the formaldehyde distillation is completed and the mixturethen poured into ice and 200 ml. of concentrated sulfuric acid, stirredand cooled to about 5 C. The crude solid is then filtered,recrystallized from water and dried at 40 C. in vacuo. The solid is thenpurified by treating with benzene, dissolving in hot water andextracting once again With benzene until aqueous layer is colorless. Theaqueous solution is cooled and precipitate filtered to yield2-p-nitrophenylacrylic acid.

21.1 g. of 2-p-nitrophenylacrylic acid and 50 ml. of acetyl chloride iswarmed gently until a solution results. The clear solution is refluxedfor about an hour and the excess acetyl chloride distilled off underreduced pressure. 100 ml. of thionyl chloride is added to the residualoil and the mixture refluxed for about an hour. The excess thionylchloride is distilled off, 3 separate portions of benzene added and alsodistilled oif. 20.0 g. of tropine hydrobromide in 35 ml. of dry pyridineis then added and heated for one hour. The mixture is cooled to about 10C., water is added and the solid filtered and then recrystallized fromwater. The impure salt is dissolved in water and made basic with 1 Nsodium hydroxide and extracted with ether. The ether solution is washedwith water and dried over anhydrous magnesium sulfate to yield3-tropanyl-2-p-nitrophenylacrylate.

An ethereal solution of the free base is treated with hydrogen chlorideto yield the hydrochloride salt.

A solution of g. of 3-tropanyl-2-p-nitrophenylacrylate hydrochloride in150 ml. of methanol is hydrogenated over Raney nickel. The reactionmixture is warmed and filtered. The precipitate which results on coolingis recrystallized from ethanol to yield 3-tro'panyl-2-p-aminophenylacrylate hydrochloride.

Example 4 A mixture containing 7.7 g. of3-tropanyl-2-p-nitrophenylacrylate hydrochloride (as prepared in Example3), 4.72 g. of isobutyraldehyde and 0.436 g. of sodium acetate in 100ml. of methanol is hydrogenated over Raney nickel. The resulting freebase is distilled to give 3-tropanyl-2-pisobutylaminophenylacrylatehaving a boiling point of about 200 C. at 0.03 mm.

Example 5 A mixture containing 10.0 g. of3-tropanyl-2-p-nitrophenyl-3-phenylacrylate hydrochloride (as preparedin Example 1), 6.1 g. of acetaldehyde and 0.55 g. of sodium acetate in250 ml. of methanol is hydrogenated over Raney nickel. The resultingfree base is distilled to yield3-tropanyl-2-p-ethylaminophenyl-3-phenylacrylate.

Example 6 To a mixture containing 30.0 g. of m-nitrophenylacetic acid,14.5 ml. of Z-furfural and 24.4 ml. of triethylamine is added 66.4 ml.of acetic anhydride. The mixture is heated on an oil bath at 100 C. forabout one hour, cooled to room temperature and taken up in acetone. Thesolution is heated with activated carbon, filtered and the acetoneevaporated. The mixture is then acidified with concentrated hydrochloricacid, cooled and filtered. The crude acid is recrystallized twice fromalcohol to yield 2-m-nitrophenyl-3-(2-furyl)acrylic acid.

A suspension of 14.5 g. of 2-m-nitrophenyl-3-(2-furyl) acrylic acid,10.0 ml. of thionyl chloride and ml. of dry benzene is warmed gentlyuntil a solution results. The clear solution is refluxed for about anhour and the excess thionyl chloride and benzene is removed. Thesolution is further washed with three portions of dry benzene. To theresulting oil is added 11.5 g. of tropine hydrobromide and the mixtureis then chilled. To this mixture is added 25 ml. of dry pyridine and thesolution is stirred for about /2 hour at room temperature and then at 60C. to 70 C. for one hour. The mixture solidifies during this process and25 ml. of dry pyridine is added. Then 100 ml. of water is added and thesolution warmed and treated with charcoal. The solution is made basicand the free base is extracted with ether and dried. The pyridine isremoved by tratement with several portions of benzene. The benzene isdistilled off to yield 3-tropanyl-2-m-nitrophenyl-3-(2- furyl)acrylate.

An acetone solution of the free base is reacted with succinic acid toyield the succinate salt.

A solution of 10 g. of 3-tropanyl-2-m-nitrophenyl-3- (2-furyl)acrylatesuccinate in 200 ml. of methanol is hydrogenated over Raney nickel. Thereaction mixture is warmed and then filtered. The precipitate formed oncooling is recrystallized from ethanol to yield 3-tropanyl-2-m-aminophenyl-3- Z-furyl acrylate maleate.

Example 7 To a mixture containing 60.0 g. of p-nitrophenylacetic acid,32.1 ml. of thiophenealdehyde and 48.2 ml. of triethylamine is added 120ml. of acetic anhydride. The mixture is heated at 150 C. for about /2hour cooled to room temperature. The liquid is acidified withconcentrated hydrochloric acid and the precipitated crude acid isextracted with 300 ml. of methylene chloride. The methylene chloridesolution is washed with about 500 ml. of water and then extractedseveral times with 2% sodium hydroxide and the basic solution cooled inice. The solution is acidified with glacial acidic acid, cooled to 5 C.,and the acid filtered and dried. The acid is recrystallized from alcoholto yield 2-p-nitrophenyl-3-(Z-thienyl)acrylic acid.

A suspension of 27.2 g. of 2-p-nitrophenyl-3-(Z-thienyl) acrylic acid,10.0 ml. of thionyl chloride and 15 ml. of dry benzene is warmed gentlyuntil a solution results. The clear solution is refluxed for about anhour and the excess thionyl chloride and benzene is removed. Thesolution is further washed with three portions of dry benzene. To theresulting oil is added 9.95 g. of tropine hydrobromide and the mixtureis then cooled. To this mixture is added 15 ml. of dry pyridine and thesolution is stirred for about A2 hour at room temperature and then at 60C. to 70 C. for one hour. The mixture solidifies during this process and30 ml. of dry pyridine is added. Then ml. of water is added and thesolution warmed and treated with charcoal. The solution is made basicand the free base is extracted with ether and dried. The pyridine isremoved by treatment with several portions of benzene. The benzene isdistilled off to yield 3-tr0panyl-2-p-nitrophenyl-3- 3-thienyl)acrylate.

An acetone solution of the free base is reacted with ethyl bromide toyield the ethobromide quaternary salt.

A solution of 5 g. of 3-tropanyl-2-p-nitrophenyl-3-(2- thienyl)acrylateethobromide in 100 ml. of methanol is hydrogenated over Raney nickel.The reaction mixture is warmed to dissolve the formed solid and thesolution is filtered to yield 3-tropanyl-2-p-aminophenyl-3-(Z-thienyl)acrylate ethobromide.

Example 8 To a mixture containing 30.0 g. of rn-nitrophenylacetic acid,18.5 g. of 4-pyridylcarboxaldehyde, 24.4 ml. of triethylamine is added66.4 ml. of acetic anhydride. The mixture is stirred for approximatelyone hour at room temperature. The solution is cooled and made aceticwith concentrated hydrochloric acid. The crude acid is filtered, driedand recrystallized from alcohol to yield.2-m-nitrophenyl-3-(4-pyridyl)acrylic acid.

A suspension of 15.0 g. of 2-m-nitrophenyl-3-(4-pyridyl) acrylic acid,20 ml. of thionyl chloride and 40 ml. of dry benzene is warmed gentlyuntil a solution results. The

clear solution is refluxed for about an hour and the excess thionylchloride and benzene is removed. The solution is further washed withthree separate portions of dry benzene. To the resulting oil is added10.0 g. of tropine hydrobromide and the mixture is then chilled. To thismixture is added 25 ml. of dry pyridine and the solution is stirred forabout /2 hour at room temperature and then at 60 C. to 70 C. for onehour. The mixture solidifies during this process and 30 ml. of drypyridine is added. Then 100 ml. of water is added and the solutionwarmed and treated with charcoal. The solution is made basic and thefree base is extracted with ether and dried. The pyridine is removed bytreatment with several portions of benzene. The benzene is distilled offto yield 3-tropanyl-2 m-nitrophenyl-3- (4-pyridyl) acrylate.

Reacting the free base with bismethylene-salicyclic acid in ethylacetate solution results in the bismethylenesalicylate salt.

A solution of 20.0 g. of the resulting salt is hydrogenated over Raneynickel to yield 3-tr0panyl-2-m-aminophenyl-3(4-pyridyl)acrylatebismethylene salicylate.

Example 9 A suspension of 26.0 g. of 2-m-nitrophenyl-3-phenylacrylicacid, as prepared in Example 2, 40 ml. of dry benzene and 20 ml. ofthionyl chloride is warmed gently until a solution results. The clearsolution is refluxed for about an hour and the excess thionyl chlorideand benzene is removed by aspirator. The solution is further Washed withthree separate portions of dry benzene. To the resulting oil is added18.2 g. of thiotropine hydrobromide and the mixture is then chilled. Tothis mixture is added 40 ml. of dry pyridine and the solution is stirredfor about /2 hour at room temperature and then at 60 C. to 70 C. for onehour. The mixture solidifies during this process and 20 ml. of drypyridine is added. Then 200 ml. of water is added and the solutionwarmed and treated with charcoal. The solution is made basic and thefree base is extracted with ether and dried. The pyridine is removed bytreatment with several portions of benzene. The benzene is distilled offto yield 3-thiotropanyl-2-m-nitrophenyl-3-phenylacrylate.

Reacting an ethereal solution of the free base with hydrogen chlorideyields the hydrochloride salt.

A solution of 10.5 g. of 3-thiotropanyl-Z-m-nitrophenyl-3-phenylacrylate hydrochloride in 200 ml. of methanol is hydrogenatedover Raney nickel. The solution is filtered and upon cooling the productis precipitated. The precipitate is recrystallized from methanol toyield 3-thiotropanyl-2-m-aminophenyl 3 phenylacrylate hydrochloride.

What is claimed is:

1. A chemical compound of the formula or a pharmaceutically acceptableacid addition salt thereof, in which:

X is oxygen; R and R are respectively hydrogen or a lower alkyl groupcontaining from 1 to 4 carbon atoms; and R is hydrogen, phenyl, 2-furyl,Z-thienyl or 2- and 4- pyridyl. 2. A chemical compound in accordancewith claim 1 in which X is oxygen.

3. A chemical compound in accordance with claim 2 in which R is phenyl.

4. A chemical compound in accordance with claim 3 in which R and R areboth hydrogen.

5. A chemical compound in accordance with claim 2 in which R R and R arehydrogen.

6. A chemical compound in accordance with claim 2 in which R and R arehydrogen and R is isobutyl.

References Cited Dyson et 211.: Chemical Abstracts, vol. 65, par. 761-hto 762c, July (1966).

JOHN D. RANDOLPH, Primary Examiner ALAN L. ROTMAN, Assistant ExaminerU.S. Cl. X.R.

